Preparation of substituted-2-4 dioxohexahydropyrimidines



United States Patent No Drawing. Continuation-impart of application Ser.No.

389,460, Aug. 13, 1964. This application Jan. 15, 1968, Ser. No. 697,606US. Cl. 260-260 7 Claims Int. Cl. C07d 51/36 ABSTRACT OF THE DISCLOSURESubstituted-24 dioxoheXahydropy-rimidines are prepared by reacting acarbamic acid ester with a beta amino ester in the presence of a Lewisacid catalyst at a temperature in the range of about 70 to 200 C. Thus,l-benzyl-3-cyclohexyl 2,4 dioxohexahydropyrimidine is prepared by thereaction of methyl-fi-benzylaminopropionate and methyl N-cyclohexylcarbamate utilizing dibutyl tin oxide as the catalyst.

This application is a continuation-in-part of Ser. No. 389,460, filedAug. 13, 1964 and now abandoned.

BACKGROUND OF THE INVENTION Substituted-2-4 dioxohexahydropyrimidinesfind increasing use as pharmaceuticals, see e.g., US. Patent No.

Conventional methods of preparation present problems such as processeconomics, including raw materials, and product work up.

SUMMARY OF THE INVENTION It has now been found that substituted-24dioxohexahydropyrirnidines having the formula can be prepared byreacting a carbamic acid ester having the formula R NHCOOR II with abeta-aminoester having the formula HNR (CH COOR III wherein R and R areradicals selected from the group consisting of alkyl radicals havingfrom 1 to 22 carbon atoms, aryl, alkaryl, aralkyl, alicyclic radicalshaving no more than 10 carbon atoms, and H radicals; and R and R arealkyl radicals whose alkanol is lower boiling than the carbamic acidester. Further details are supplied below.

The ring closure of the nature presented has not been previouslyreported.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The equation for the reactionis illustrated below.

3,422,108 Patented Jan. 14, 1969 "ice the examples and in Table I.

The R and R radicals are alkyl radicals having from 1 to 12 carbon atomswith methyl and ethyl preferred. The'R R R and R radicals can thus bethe same or different.

In the case of the aminoesters, it is possible to change the number ofthe methylene groups and also by adding substituents thereon, to formfurther heterocyclic N rings.

The reactants are employed in about stoichiometric amounts. Temperaturesin the range of about 7 0-220 C., preferably -150 C., are employed withpressures of atmospheric or less as required to maintain the temperatureand alcohol evolution. In general, higher temperatures within the rangeare employed at the terminal portion of the reaction and when theindicated radicals are not H, i.e., R radical.

Inert organic diluents such as, e.g., naphtha, xylene, andchlorobenzene, or none, can be employed. Excess of one reactant,preferably carbamic acid ester, can be used as the diluent.

A minor amount of a metal compound Lewis acid catalyst is employed suchas dibutyl tin oxide, titanium tetrachloride, cupric acetate, stannicchloride, stannous oxalate, aluminum alkoxide, and alkyl tin oxides. Thecatalyst is used in an amount of from about 0.1-2 wt. percent based onaminoester.

This invention, product work up, and its advantages will be betterunderstood by reference to the following examples.

EXAMPLE 1 Preparation of 1-cyclohexyl-2,4-dioxohexahydropyrimidine:

Methyl-,S-cyclohexylaminopropionate (93 g., 0.5 mole) and methylcarbamate (42 g., 0.55 mole) were heated in xylene (25 ml.) in thepresence of stannic chloride (2.0 g.) at -130 C. and approximately 200mm. pressure. Methanol formed from the reaction was distilled out over aperiod of four hours, at which time the reaction was complete. Twohundred ml. butanol were added, the mixture heated to solution, carbontreated and filtered. The product was crystallized, filtered and washed.There were obtained 47 g. (48% of theory) of1-cyclohexyl-2,4-dioxohexahydropyrimidine.

EXAMPLE 2 Preparation of1-benzyl-3-cyclohexyl-2,4-dioxohexahydropyrimidine:

Methyl-fi-benzylaminopropionate (38 g, 0.2 mole) and methyl N-cyclohexylcarbamate (34.5 g., 0.22 mole) were heated in xylene ml.) in thepresence of dibutyl tin oxide (0.5 g.) at 150 C. for two hours,meanwhile distilling one-half of the theoretical methanol. Thetemperature was then raised to 210 C. by distillation of the xylene.Under these conditions, ring-closure occurred and the remaining methanolwas removed. Xylene (150 ml.) was added and the mixture cooled andcrystallized. There 4 a were obtained 1 8g. (31%) ofl-benzyl-3-cyclohexyl-2,4- ing the formula: HNR (CH COOR wherein R anddioxohexahydropyrimidine. R are radicals selected from the groupconsisting of alkyl Further experimental results are summarized in Tableradicals having up to four carbon atoms, phenyl fl-phenyl,

I. R and R were methyl except as indicated. The lM.P.s3,4-dichloro-a-phenethyl, cyclohexyl and H radicals; and and analysesare reported for samples recrystallized once 5 R and R are alkylradicals, having from 1 to 12 carbon from xylene or butanol solvent.Similar results are obatoms, whose alkanol is lower boiling than thecarbamic tained from other suitable solvents and catalysts. acid ester,in the presence of a Lewis acid catalyst selected TABLE I Yield PurityNo. R; R; Catalyst (percent of M.P. (percent) theory) 4 Butyl 70 80.0-81.7 101.6 5 Cyclohexyl H 48 183. O185.0 100.2 31 s. 5-211. 0 97. 5

"'70 "1153:1263 iif Used butyl carbamate.

These data show the operability of the claimed process from the groupconsisting of dibutyl tin oxide, titanium with a variety of reagents.Yields can readily be improved tetrachloride, cupric acetate, stannicchloride, stannous by optimizing of conditions. oxalate, aluminumalkoxide, and alkyl tin oxides, utilized The advantages of thisinvention will be apparent to in an amount of from 0.1 to 2.0 wt.percent based on the skilled in the art. An economical process is madeaminoester, at a temperature in the range of about 70- available forreadily preparing the desired products with 220 C. and recovering thesubstituted-2,4 dioxyhydroyields equal or better than previouslypossible. pyrimidine.

It is to be understood that this invention is not limited 2, The processof laim :1 i whi h the R i benzyl, the to the specific examples whichhave been offered merely R is cyclohexyl and R and R are methyl. asillustrations, and that modifications can be made with- 3, Th process ofl i 1 i hi h h R i p. h out departing from the spirit thereof. ethyl,the R is H, and R and R are methyl.

What is claimed is: 4. The process of claim 1 in which the R is butyl,the

1. A process for preparing a substituted-2,4 dioxyhexa- R is H, and Rand R are methyl. hydropyrimidine having the formula: 5. The process ofclaim 1 in which the R is 3,4 dichloro-ot-phenethyl, the R is H, and Rand R are methyl. 1 6. The process of claim 1 in which the R is benzyl,the 1 R is H, and R and R are methyl. 7. The process of claim .1 inwhich the R is benzyl, the (3H1 i= R is phenyl, and R and R are methyl.CH1 N--1Et References Cited g UNITED STATES PATENTS 3,124,580 3/ 1-964Surrey et a1. 260-260 ALEX MAZEL, Primary Examiner. whlch comprlsesreacting a carbamlc acid ester having the formula: N NHCOOR with abeta-aminoester hav- ANNE MARIE TIGHE, ASSlSlant Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,422,108 January 14, 1969 Phillip Adams et a1.

It is certified that error appears in the above identified patent andthat said Letters Patent are hereby corrected as shmm below:

Column 3, last line, the formula should appear as shown below:

R NHcooR Column 4, line 3, 8-phenyl" should B-phenethyl Signed andsealed this 17th day of March 1970.

(SEAL) Attest:

WILLIAM E. SCHUYLER, JR.

Edward M. Fletcher, Jr.

Commissioner of Patents Attesting Officer

